肖恒綜述陳余清審校

(蚌埠醫(yī)學(xué)院第一附屬醫(yī)院呼吸與危重癥醫(yī)學(xué)科，安徽蚌埠233000)

·綜述·

間充質(zhì)干細(xì)胞與肺癌的相關(guān)研究進(jìn)展

肖恒綜述陳余清審校

(蚌埠醫(yī)學(xué)院第一附屬醫(yī)院呼吸與危重癥醫(yī)學(xué)科，安徽蚌埠233000)

肺癌是世界發(fā)病率最高的惡性腫瘤，已成為癌癥致病死的最主要原因。間充質(zhì)干細(xì)胞是一種無造血功能的干細(xì)胞，具有多向分化的潛能，可以分化為脂肪、軟骨、骨等多種組織。近年的研究發(fā)現(xiàn)間充質(zhì)干細(xì)胞能促進(jìn)肺癌組織的血管生成、肺癌的轉(zhuǎn)移能力及腫瘤細(xì)胞對藥物的抵抗能力，但目前其在肺癌中的具體作用機(jī)制及臨床意義尚不明確，本文就近年來有關(guān)間充質(zhì)干細(xì)胞和肺癌的相關(guān)研究進(jìn)展進(jìn)行綜述。

間充質(zhì)干細(xì)胞；肺癌；進(jìn)展

大部分的肺癌患者在確診時(shí)已失去手術(shù)的機(jī)會，導(dǎo)致肺癌的病死率較高。雖然新型化療藥物及分子靶向藥物的應(yīng)用改善了肺癌患者的生存質(zhì)量并延長了生存期，但肺癌患者的總生存期依然很短。肺癌的發(fā)生、發(fā)展并不是完全由肺癌細(xì)胞決定，許多腫瘤微環(huán)境中的非腫瘤細(xì)胞也影響著腫瘤的發(fā)生。肺癌周圍的細(xì)胞，包括基質(zhì)細(xì)胞、細(xì)胞因子、炎癥因子、趨化因子等共同構(gòu)成了肺癌的微環(huán)境并影響著肺癌的增殖、生長、轉(zhuǎn)移和耐藥。人間充質(zhì)干細(xì)胞(human mesenchymal stem cells，hMSCs)來源于發(fā)育早期的外胚層和中胚層，為非造血干細(xì)胞，骨髓、脂肪、臍帶等組織均可培養(yǎng)出間充質(zhì)干細(xì)胞。間充質(zhì)干細(xì)胞具有多向分化的潛能，不同的誘導(dǎo)條件可使其分化為多種組織細(xì)胞。作為大多數(shù)基質(zhì)細(xì)胞的前體細(xì)胞，間充質(zhì)干細(xì)胞是腫瘤微環(huán)境的重要組成部分，可以通過再循環(huán)的途徑到達(dá)腫瘤病灶，形成腫瘤微環(huán)境，參與了包括肺癌在內(nèi)的多種類型的腫瘤疾病的發(fā)生和發(fā)展。為進(jìn)一步研究間充質(zhì)干細(xì)胞提供思路，本文就近年來有關(guān)間充質(zhì)干細(xì)胞和肺癌的相關(guān)研究進(jìn)展進(jìn)如下綜述：

1 間充質(zhì)干細(xì)胞對肺癌生長的作用

越來越多的證據(jù)表明，間充質(zhì)干細(xì)胞表現(xiàn)出減少肺癌細(xì)胞凋亡及促進(jìn)肺癌生長的能力。在Transwell體系中饑餓的肺癌細(xì)胞株A549和間充質(zhì)干細(xì)胞共培養(yǎng)后，肺癌細(xì)胞獲得更好的增殖能力，細(xì)胞凋亡率降低，肺癌細(xì)胞的自噬發(fā)生率升高。這提示間充質(zhì)干細(xì)胞誘導(dǎo)自噬的發(fā)生可能與通過抑制Bcl-2(B細(xì)胞淋巴瘤/白血病-2)的表達(dá)，增加自噬相關(guān)調(diào)節(jié)因子beclin-1表達(dá)相關(guān)[1]。間充質(zhì)干細(xì)胞與Lewis肺癌細(xì)胞共注射至C57BL/6小鼠后，可以觀察到間充質(zhì)干細(xì)胞促進(jìn)了腫瘤的血管生成進(jìn)而促進(jìn)腫瘤的生長[2]。同時(shí)，有證據(jù)表明間充質(zhì)干細(xì)胞通過自發(fā)的分化參與癌癥發(fā)生的早期階段。體內(nèi)外的實(shí)驗(yàn)結(jié)果均提示間充質(zhì)干細(xì)胞在長期的培養(yǎng)過程中出現(xiàn)染色體異變隨后產(chǎn)生惡性分化[3]。Gottschling等[4]的研究表明肺癌組織來源的MSC(NSCLC-MSC)的增殖能力高于正常肺組織MSC(NLT-MSC)，NSCLC-MSC有62個(gè)基因表達(dá)，不同于NLT-MSC，涉及細(xì)胞增殖、DNA修復(fù)、細(xì)胞外基質(zhì)合成、組織重塑和血管生成等。而且腫瘤細(xì)胞的條件培養(yǎng)液可以刺激MSC高表達(dá)腫瘤相關(guān)成纖維細(xì)胞(cancer-associated fibroblasts，CAF)的標(biāo)志物α的平滑肌肌動蛋白(α滑肌肌動蛋白(ssociated fib，α肌肌動)，提示MSC可能是肺癌組織腫瘤相關(guān)成纖維細(xì)胞的前體細(xì)胞。另一方面，亦有許多報(bào)道指出間充質(zhì)干細(xì)胞抑制肺癌的生長。Tian等[5]的實(shí)驗(yàn)結(jié)果顯示間充質(zhì)干細(xì)胞可能通過下調(diào)PCNA(增殖細(xì)胞核抗原)、Bcl-2(B細(xì)胞淋巴瘤/白血病-2)的表達(dá)，抑制CDK2(細(xì)胞周期依賴性激酶2)復(fù)合物的形成來抑制A549肺癌細(xì)胞的增殖并誘導(dǎo)其凋亡。此外，在腫瘤微環(huán)境中，NF-κB信號通路通過抗凋亡蛋白的轉(zhuǎn)錄調(diào)控腫瘤細(xì)胞的增殖，促進(jìn)很多類型的腫瘤生長和轉(zhuǎn)移，脂肪來源的間充質(zhì)干細(xì)胞可以通過阻斷NF-κB信號通路來抑制肺癌的生長[6]。引起上述體內(nèi)外不同結(jié)果的原因可能是當(dāng)間充質(zhì)干細(xì)胞與肺癌細(xì)胞接觸后產(chǎn)生了促進(jìn)肺癌生長的物質(zhì)。反之，當(dāng)間充質(zhì)干細(xì)胞沒有受到肺癌細(xì)胞的影響時(shí)就不會產(chǎn)生促癌物質(zhì)，也就不會誘導(dǎo)肺癌的形成[7]。

2 間充質(zhì)干細(xì)胞參與了肺癌的遠(yuǎn)處轉(zhuǎn)移

腫瘤細(xì)胞從原發(fā)病灶播散至其他組織是一個(gè)復(fù)雜的過程，包括：原發(fā)腫瘤的生長、腫瘤細(xì)胞脫離、入侵淋巴系統(tǒng)或血管、通過循環(huán)粘附定植在實(shí)質(zhì)組織、降解基底膜、最終形成轉(zhuǎn)移病灶。細(xì)胞外基質(zhì)成分(ECM)的降解是這個(gè)過程中的關(guān)鍵環(huán)節(jié)，肺癌細(xì)胞株A549在間充質(zhì)干細(xì)胞間接共培養(yǎng)作用下對ECM的破壞能力有所下降提示間充質(zhì)干細(xì)胞可能抑制肺癌細(xì)胞的侵襲和轉(zhuǎn)移能力[1]。E-鈣粘蛋白(E-cadherin)是一種鈣依賴細(xì)胞分子，對保持上皮來源細(xì)胞的結(jié)構(gòu)和完整性具有重要作用[8]，研究已證實(shí)，E-鈣粘蛋白表達(dá)降低或丟失通過使細(xì)胞間連接丟失、誘導(dǎo)細(xì)胞發(fā)生EMT (上皮-間質(zhì)轉(zhuǎn)化)等而啟動細(xì)胞轉(zhuǎn)移[9]。而間充質(zhì)干細(xì)胞通過下調(diào)肺癌細(xì)胞E-鈣粘蛋白的表達(dá)水平可能是其促進(jìn)肺癌轉(zhuǎn)移的方式之一。Do等[10]發(fā)現(xiàn)從脂肪組織中提取的間充質(zhì)干細(xì)胞暴露于A549的分泌物質(zhì)后可轉(zhuǎn)換成腫瘤相關(guān)成纖維細(xì)胞(CAFs)。腫瘤相關(guān)成纖維細(xì)胞可以通過誘導(dǎo)EMT，上調(diào)α上調(diào)細(xì)胞、成纖維細(xì)胞活化蛋白(FAP)、SMAD3的表達(dá)和活化hedgehog信號通路增強(qiáng)肺癌細(xì)胞的增殖、生長及轉(zhuǎn)移[11-13]。

3 間充質(zhì)干細(xì)胞在肺癌耐藥中的作用

細(xì)胞因子、炎癥因子、細(xì)胞之間和細(xì)胞-基質(zhì)間粘附分子及缺氧條件共同構(gòu)成的腫瘤微環(huán)境賦予了腫瘤細(xì)胞的耐藥特性。許多的研究表明間充質(zhì)干細(xì)胞通過直接增強(qiáng)腫瘤細(xì)胞的耐藥能力或間接調(diào)控腫瘤微環(huán)境相關(guān)因子的方式參與構(gòu)建了有利于腫瘤細(xì)胞耐藥的微環(huán)境[14-15]。有報(bào)道指出，間充質(zhì)干細(xì)胞可以減弱順鉑對Lewis肺癌細(xì)胞的作用[16]。Hsu等[17]發(fā)現(xiàn)肺癌細(xì)胞株A549或CL1-5與間充質(zhì)干細(xì)胞共培養(yǎng)后通過活化IL-6/JAK2/STAT3信號通路使癌球增大、癌細(xì)胞產(chǎn)生耐藥及過表達(dá)多能標(biāo)記物。Bergfeld等[18]發(fā)現(xiàn)間充質(zhì)干細(xì)胞可以歸巢至肺癌病灶并顯著降低紫杉醇或阿霉素誘導(dǎo)的肺癌細(xì)胞的凋亡，表明了間充質(zhì)干細(xì)胞在肺癌的耐藥中可能發(fā)揮了重要的作用。此外，非小細(xì)胞肺癌組織中提取的間充質(zhì)干細(xì)胞顯示出較正常肺組織更強(qiáng)的耐鉑類藥物的特性[19]。由于MSCs可以分化成腫瘤相關(guān)成纖維細(xì)胞，有研究表明腫瘤相關(guān)成纖維細(xì)胞可使肺癌細(xì)胞產(chǎn)生對EGFR受體拮抗劑吉非替尼的耐藥性[20]。因此，間充質(zhì)干細(xì)胞可能會降低肺癌對EGFR受體拮抗劑的敏感性。

4 間充質(zhì)干細(xì)胞在肺癌診治中的價(jià)值

4.1 間充質(zhì)干細(xì)胞可以做為肺癌基因治療的載體間充質(zhì)干細(xì)胞被證實(shí)可向機(jī)體受損部位遷移，而且與白細(xì)胞向炎癥部位募集類似，這種遷移活動受基質(zhì)細(xì)胞衍生因子-1(SDF-1)/CXC家族細(xì)胞因子受體4 (CXCR4)軸的作用影響[21]。Nakamizo等[22]發(fā)現(xiàn)，熒光標(biāo)記的hMSCs注入神經(jīng)膠質(zhì)瘤小鼠模型的頸動脈后,不論注入腫瘤同側(cè)或者腫瘤對側(cè)均可檢測到間充質(zhì)干細(xì)胞聚集到腫瘤組織內(nèi)。Hung等[23]也發(fā)現(xiàn)，通過種植結(jié)腸癌細(xì)胞建立免疫缺陷小鼠移植瘤模型，并將熒光標(biāo)記的MSCs通過尾靜脈注入小鼠體內(nèi)，觀察MSCs在體內(nèi)的分布情況，發(fā)現(xiàn)MSCs可靶向進(jìn)入移植瘤并分化為腫瘤基質(zhì)的重要組成部分。這些研究結(jié)果說明了間充質(zhì)干細(xì)胞具有向腫瘤組織趨化遷移的能力。同時(shí)，間充質(zhì)干細(xì)胞具有來源較豐富、易于被分獲取、具有多向分化潛能、較低的免疫原性等多種優(yōu)點(diǎn)，可以被用于肺癌基因治療的載體。凋亡素修飾的間充質(zhì)干細(xì)胞在肺癌裸鼠模型中表現(xiàn)出抑制肺癌生長的作用[24]。白介素-24轉(zhuǎn)導(dǎo)的人臍帶來源的間充質(zhì)干細(xì)胞作用于肺癌A549細(xì)胞可以產(chǎn)生抗血管生成的效應(yīng)，通過抑制ERK-1/2和AKT磷酸化、促進(jìn)JNK磷酸化、增加Caspases-3/8/9的活性，改變抗凋亡蛋白/促凋亡蛋白(Bax/Bcl-2)的比例，在體內(nèi)外顯著抑制肺癌細(xì)胞的生長[25]。Matsuzuka等[26]的研究表明用IFN-明轉(zhuǎn)染的人臍帶來源的間充質(zhì)干細(xì)胞可以抑制肺腺癌細(xì)胞株H358在體外的增殖并在體內(nèi)抑制腫瘤的生長。在其他腫瘤中MSCs的類似作用還有經(jīng)過NK細(xì)胞和T細(xì)胞的趨化因子CX3CL1及肝細(xì)胞生長因子拮抗體修飾的MSCs作用于小鼠腫瘤模型后可以抑制轉(zhuǎn)移瘤的形成并延長小鼠的生存期[27-28]。可見利用間充質(zhì)干細(xì)胞作為載體的基因治療已經(jīng)被廣泛的應(yīng)用至臨床實(shí)踐中。

4.2 間充質(zhì)干細(xì)胞可能會減輕放療及化療引起的副作用在肺癌的治療方法中，尤其是對晚期的肺癌患者，放射治療是一個(gè)重要的治療手段。然而，放射治療會引起放射性肺炎與肺纖維化[29]。放射治療誘導(dǎo)的肺損傷的確切機(jī)制是未知的，可能涉及促炎性和促纖維化分子的釋放，從而導(dǎo)致成纖維細(xì)胞的增殖和細(xì)胞外基質(zhì)的過度沉積[30]。由于間充質(zhì)干細(xì)胞可以歸巢至放療損傷的肺組織[31]，可能為減輕肺癌患者放療后引起的副作用提供一個(gè)潛在的治療方法。在體外實(shí)驗(yàn)中，間充質(zhì)干細(xì)胞可以保護(hù)由放射線引起的Ⅱ型肺泡上皮細(xì)胞的凋亡；在小鼠體內(nèi)，間充質(zhì)干細(xì)胞能夠向射線誘導(dǎo)的肺損傷組織遷移并且減少射線誘導(dǎo)的肺損傷造成的死亡[32-33]。另外，Di等[34]提出間充質(zhì)干細(xì)胞可以修復(fù)阿霉素引起的心肌損傷及減少阿霉素引起的腸腺細(xì)胞的凋亡。Ortiz等[35]證實(shí)間充質(zhì)干細(xì)胞可以歸巢至博來霉素?fù)p傷的肺組織并減輕損傷部位的炎癥及膠原沉積。因此，間充質(zhì)干細(xì)胞可能會減輕肺癌患者放療和化療引起的副作用。

5 展望

綜上所述，間充質(zhì)干細(xì)胞在肺癌的生長、轉(zhuǎn)移、耐藥等多個(gè)過程中發(fā)揮重要的作用，但是間充質(zhì)干細(xì)胞和肺癌的關(guān)系目前仍不明確，并且間充質(zhì)干細(xì)胞在肺癌的發(fā)生發(fā)展過程中的作用依然存在爭議。這些爭議產(chǎn)生的原因可能與宿主的免疫狀態(tài)、不同的腫瘤細(xì)胞和腫瘤微環(huán)境及其他未知的因素有關(guān)?；陂g充質(zhì)干細(xì)胞可以歸巢至腫瘤部位的特性，明確間充質(zhì)干細(xì)胞與肺癌的關(guān)系及如何安全有效的利用間充質(zhì)干細(xì)胞作為肺癌基因治療的載體仍需要在其安全性、靶向性、可控性等方面進(jìn)一步研究。同時(shí)，由于間充質(zhì)干細(xì)胞可以減輕放射治療及化療所帶來的肺部損傷，間充質(zhì)干細(xì)胞在用于治療放化療引起的肺損傷方面同樣顯示出了良好的前景。

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Research progress of mesenchymal stem cells and lung cancer.

XIAO Heng,CHEN Yu-qing.Department of Respiratory Medicine,the First Affiliated Hospital of Bengbu Medical College,Bengbu 233000,Anhui,CHINA

Lung cancer is the world's highest incidence of malignant tumor,which has become the leading cause of death.Mesenchymal stem cells(MSCs)are a kind of non-hematopoietic stem cell.They have the potential to differentiate into multiple tissues such as fat,cartilage and bone.Recent studies have shown that MSCs can promote the angiogenesis and metastasis ability of lung cancer as well as the drug resistance of tumor cells,but its specific mechanism and clinical significance in lung cancer is not clear.In this paper,recent advances in mesenchymal stem cells and lung cancer are reviewed.

Mesenchymal stem cells(MSCs);Lung cancer;Progress

10.3969/j.issn.1003-6350.2017.10.031

R734.2

A

1003—6350（2017）10—1641—04

2016-10-18)

安徽省自然科學(xué)基金青年項(xiàng)目（編號：1608085QH189）；蚌埠醫(yī)學(xué)院2015年研究生科研創(chuàng)新計(jì)劃立項(xiàng)項(xiàng)目（編號：Byycxz1502）

陳余清。E-mail：bbmccyq@126.com